The background description includes information that may be useful in understanding the present inventive subject matter. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventive subject matter, or that any publication specifically or implicitly referenced is prior art.
All publications and patent application identified herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Rendering cancer cells ‘visible’ to an immune system has become a promising avenue in immune therapy and typically requires transformation or otherwise manipulating cells to increase the visibility of cancer cells to the immune system. For example, immune competent cells, and especially dendritic cells can be transformed to express recombinant cancer related proteins (e.g., neoepitopes), which typically requires bacterial, yeast, or viral gene expression systems that tend to be relatively large and therefore require dedicated delivery techniques (e.g., viral transfection, lipofection, etc.). In other examples, cancer cells can be treated with various chemicals to trigger the cells to produce surface markers that increase the visibility of cancer cells to the immune system. Unfortunately, the delivery of cargo material into cells is often problematic, particularly where delivery is to be performed at a relatively large scale while maintaining viability of the treated cells.
For example, U.S. Pat. No. 8,080,399 describes using a Bessel beam of a laser to create a pore in a cell membrane. Notably, the same beam is also required to trap or manipulate the material for introduction into the cell. Although useful for targeted delivery of material into a single cell, such approach does not scale for bulk manipulation of cells. In another example, US 2011/0111002, glutathione coated nanoparticles are employed to import glutathione into a cell. While conceptually relatively simple, such approach requires transmembrane transport of the nanoparticle, which is typically not very efficient. To increase efficiency, nanoparticles were used to generate cavitation bubbles to temporarily open cell membranes as is taught in CN 102776237. Similarly, US 2013/0113140 describes use of nanoparticles to generate a cavitation event that is triggered by laser induced breakdown of the nanoparticles. Here, the nanoparticles are optically trapped as single nanoparticles. Consequently, such methods are not suitable for large scale transfection of a relatively large number of cells.
More recently, efforts have been made toward modifying certain cells to specifically induce some form of immune response. For example, CN 103908468 teaches that cGAMP could be used to prepare injectable anti-tumor compositions. Similarly, WO 2015/077354 describes administration of stimulator of interferon genes (STING) agonists intra-tumorally. Likewise, US 2014/0329889 discloses triggering of type I interferon by increasing cyclic-di-nucleotides within a cell. However, such attempts again require transmembrane transport of the therapeutic entities and as such efficacy is relatively low. Moreover, due to the limited approaches in transfecting cells with therapeutic entities, large scale preparation of cells with an induced innate immune response have remained elusive.
Thus there remains a need for efficient delivery of therapeutic entities, and especially triggers of an innate immune response into target cells, particularly where such target cells are then employed as cellular therapeutics.